Project Summary Many regions of the brain including the cortex, hippocampus, basal ganglia, and limbic structures are highly enriched with synaptic zinc. Synaptic zinc (as Zn2+) is loaded into presynaptic vesicles by zinc transporter 3 (ZnT3), where it is coreleased with glutamate during synaptic transmission. Since synaptic zinc inhibits AMPA and NMDA receptors ? which mediate the majority of excitatory glutamatergic transmission in the brain ? synaptic zinc can modulate excitatory synaptic signaling. ZnT3 KO mice (which lack synaptic zinc) display a range of cognitive and sensory impairments and demonstrate behavioral deficits associated with autism and schizophrenia. Mounting evidence from human populations shows that mutations in certain zinc transporters are linked with major neurological disorders such as schizophrenia. Together, these findings strongly suggest that synaptic zinc signaling is important for neuronal processing. The goals of this project are to understand how synaptic zinc contributes to normal neuronal function and how disruptions in zinc signaling are linked to pathological neuronal conditions. We will take three complimentary experimental approaches to these questions. 1) Using ex vivo brain slice preparations and optogenetic stimulation paradigms, we dissect the roles of synaptic zinc in shaping the dynamics of synaptic transmission at specific synaptic connections in cortical microcircuits. 2) Using in vivo 2-photon calcium imaging, we assess the roles of synaptic zinc in shaping the sensory-evoked responses of specific classes of auditory cortical neurons in awake mice. 3) Using in vitro high-throughput screening assays and rational compound design approaches, we are designing novel tools to modulate the function of specific zinc transport proteins. Together these approaches will allow us to answer fundamental questions concerning the role of synaptic zinc in brain function and provide new mechanistic insights into endogenous mechanisms that shape synaptic and neural processing.